Analysis Tools
cellular
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• mice show normal sensitivity to acute treatment with 7.5 Gy of ionizing radiation and MEFs do not show increased cellular sensitivity to ionizing radiation
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• MEFs exhibit more nuclear abnormalities, such as micronuclei and nuclear budding indicating that resolving DNA replication stress is impaired
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• primary MEFs show increased chromosome aberrations
• MEFs treated with aphidicolin exhibit greatly increased chromosome aberrations
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• MEFs exhibit nuclear bridges between segregating chromosomes during anaphase
• more than 20% of cells contain ultrafine bridges formed in mitosis
• G1 cells exhibit an increase in the frequency of cells containing 53BP1 nuclear bodies and the number of 53BP1 bodies per cell; formation of 53BP1 bodies is associated with fragile sites and difficult to replicate regions of the genome
• percentage of cells containing 53PB1 nuclear bodies and the number of 53BP1 bodies per cell are greatly increased with MEFs treated with aphidicolin
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• MEFs are hypersensitive to the DNA cross-linking agent mitomycin C
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• MEFs are hypersensitive to ultraviolet radiation
• however, MEFs do not show increased cellular sensitivity to ionizing radiation
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• MEFs treated with a low dose of a DNA polymerase inhibitor, aphidicolin, to mimic the physiological barriers that the DNA replication machinery approaches during DNA synthesis, exhibit decreased fork progression, indicating impaired response to replication stress
• however, speed of DNA replication is similar to wild-type MEFs, indicating that overall fork progression and rate are unaffected
• MEFs treated with hydroxyurea, to deplete nucleotide pools and stall replication forks, show an increase in replication stalling and extensive ssDNA formation at stalled forks and degradation of newly synthesized DNA is seen, indicating a defect of protection of nascent DNA at stalled replication forks
• hydroxyurea-treated MEFs show a dramatic increase in the frequency of forks that could not restart and collapse and for forks that resume DNA synthesis, fork progression is reduced
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• MEFs exhibit genomic instability
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homeostasis/metabolism
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• MEFs treated with a low dose of a DNA polymerase inhibitor, aphidicolin, to mimic the physiological barriers that the DNA replication machinery approaches during DNA synthesis, exhibit decreased fork progression, indicating impaired response to replication stress
• however, speed of DNA replication is similar to wild-type MEFs, indicating that overall fork progression and rate are unaffected
• MEFs treated with hydroxyurea, to deplete nucleotide pools and stall replication forks, show an increase in replication stalling and extensive ssDNA formation at stalled forks and degradation of newly synthesized DNA is seen, indicating a defect of protection of nascent DNA at stalled replication forks
• hydroxyurea-treated MEFs show a dramatic increase in the frequency of forks that could not restart and collapse and for forks that resume DNA synthesis, fork progression is reduced
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endocrine/exocrine glands
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• 1 of 28 mice develop sebaceous adnexal tumor
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growth/size/body
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• 36% of mice exhibit enlarged spleen
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hematopoietic system
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• 36% of mice exhibit enlarged spleen
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immune system
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• 36% of mice exhibit enlarged spleen
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• mice exhibit inflammatory lymphoid infiltration in major organs suggesting infection or lymphoid proliferative diseases
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integument
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• 1 of 28 mice develop sebaceous adnexal tumor
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mortality/aging
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• mice exhibit reduced life span and decreased disease-free survival
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neoplasm
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• mice exhibit an increase in tumor incidence, although tumor frequency is low (21%) and latency is long
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• 1 of 28 mice develop sebaceous adnexal tumor
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• 4 of 28 mice develop lymphoma
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• 1 of 28 mice develop lung adenocarcinoma
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respiratory system
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• 1 of 28 mice develop lung adenocarcinoma
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